C-nitroso-derived nitroxyl donors

ABSTRACT

Active compounds of Formula I are described: 
     
       
         
         
             
             
         
       
     
     wherein: R 1  and R 2  are each independently C1-C4 alkyl; or R 1  and R 2  together form a C2-C7 alkylene chain; and Z is a non-steroidal anti-inflammatory drug (NSAID); along with pharmaceutically acceptable salts and prodrug thereof, and methods of using the same.

RELATED APPLICATIONS

This application claims priority to and is a continuation of U.S. patentapplication Ser. No. 12/719,778, filed on Feb. 23, 2010, now allowed,which is a continuation of U.S. patent application Ser. No. 12/293,374,filed Oct. 1, 2008, now U.S. Pat. No. 7,696,373, which is a nationalphase application of PCT Application PCT/US2007/009160, filed Apr. 13,2007, and published in English on Oct. 25, 2007, as InternationalPublication No. WO 2007/120839, and which claims the benefit under 35U.S.C. §119(e) of U.S. Provisional Patent Application Ser. No.60/744,792, filed Apr. 13, 2006, the disclosure of each of which isincorporated herein by reference in its entirety.

FIELD OF THE INVENTION

The present invention concerns C-nitroso derived nitroxyl donors,methods of making and using the same, and pharmaceutical formulationsthereof.

BACKGROUND OF THE INVENTION

NO-donors have been suggested to have antithrombotic and vasodilatingactivity. K. Rehse and M. Herpel, Arch. Pharm. Pharm Med. Chem. 331,104-110 (1998) describe on page 104 the following compounds:

additional compounds are described on page 106 in Table 1 therein.

More recently, V. Daineko et al., Russian Journal of Organic Chemistry,38, 1431-1433 (2002) describe compounds of the formula:

where (for I) R is Me, or (for II) RR is (CH₂)₅. See also E. Zhutov etal., Russian Journal of Organic Chemistry, 39, 1672-1673 (2003)

SUMMARY OF THE INVENTION

A first aspect of the invention is a compound (sometimes referred to as“active compounds” herein) of Formula I:

wherein:

R₁ and R₂ are each independently C1-C4 alkyl;

or R₁ and R₂ together form a C2-C7 alkylene chain; and

Z is a non-steroidal anti-inflammatory drug (NSAID);

or a pharmaceutically acceptable salt or prodrug thereof. A particularexample is:

or a pharmaceutically acceptable salt or prodrug thereof.

A further aspect of the present invention is an compound (sometimesreferred to as an “active compound” herein) of Formula

wherein:

R₁ and R₂ are each independently C1-C4 alkyl;

or R₁ and R₂ together form a C2-C7 alkylene chain; and

R₃ is C1-C5 alkyl, haloalkyl or aryl,

or a pharmaceutically acceptable salt or prodrug thereof.

A further aspect of the invention is a pharmaceutical composition (e.g.,for treating congestive heart failure) comprising a compound or activecompound as described herein in a pharmaceutically acceptable carrier.

A further aspect of the invention is a method of treating acardiovascular disorder such as congestive heart failure in a subject inneed thereof, comprising administering said subject atreatment-effective amount of a compound or active compound as describedherein. Optionally, the method may include concurrently administering abeta blocker to the subject in a treatment-effective amount.

A further aspect of the present invention is a method of treatinggastrointestinal side effects associated with NSAID treatment in asubject in need thereof, comprising administering said subject atreatment-effective amount of an active compound as described herein.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention is primarily concerned with the treatment of humansubjects, but the invention may also be carried out on animal subjects,particularly mammalian subjects such as mice, rats, dogs, cats,livestock and horses for veterinary purposes.

“Alkyl,” as used herein, refers to a straight or branched chainhydrocarbon containing from 1 to 10 carbon atoms. Representativeexamples of alkyl include, but are not limited to, methyl, ethyl,n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl,n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl,2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl,n-decyl, and the like. “Loweralkyl” as used herein, is a subset of alkyland refers to a straight or branched chain hydrocarbon group containingfrom 1 to 4 carbon atoms. Representative examples of lower alkylinclude, but are not limited to, methyl, ethyl, n-propyl, iso-propyl,n-butyl, iso-butyl, tert-butyl, and the like. Alkyl may be substitutedor unsubstituted unless specified otherwise and where substituted may besubstituted one or more (e.g., one, two or three times) with anothergroup such as hydroxy, halo (fluoro, chloro, bromo, iodo), nitro, amino,or the like.

“Haloalkyl” as used herein alone or as part of another group, refers toat least one halogen, as defined herein, appended to the parentmolecular moiety through an alkyl group, as defined herein.Representative examples of haloalkyl include, but are not limited to,chloromethyl, 2-fluoroethyl, trifluoromethyl, pentafluoroethyl,2-chloro-3-fluoropentyl, and the like.

“Alkylene” as used herein refers to a difunctional alkyl group where“alkyl” is as defined above. Examples include, but are not limited to,—CH₂CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂CH₂—, and —CH₂CH₂CH₂CH₂CH₂CH₂—.

“Aryl” as used herein alone or as part of another group, refers to amonocyclic carbocyclic ring system or a bicyclic carbocyclic fused ringsystem having one or more aromatic rings. Representative examples ofaryl include, azulenyl, indanyl, indenyl, naphthyl, phenyl,tetrahydronaphthyl, and the like. The term “aryl” is intended to includeboth substituted and unsubstituted aryl unless otherwise indicated andthese groups may be substituted with the same groups as set forth inconnection with alkyl and loweralkyl above.

The term “treat” as used herein refers to any type of treatment thatimparts a benefit to a patient afflicted with a disease, includingimprovement in the condition of the patient (e.g., in one or moresymptoms), delay in the progression of the disease, etc.

The term “pharmaceutically acceptable” as used herein means that thecompound or composition is suitable for administration to a subject toachieve the treatments described herein, without unduly deleterious sideeffects in light of the severity of the disease and necessity of thetreatment.

Active compounds of the present invention may optionally be administeredin conjunction with other compounds useful in the treatment ofcardiovascular disease. The other compounds may optionally beadministered concurrently. As used herein, the word “concurrently” meanssufficiently close in time to produce a combined effect (that is,concurrently may be simultaneously, or it may be two or more eventsoccurring within a short time period before or after each other).

As used herein, the administration of two or more compounds “incombination” means that the two compounds are administered closelyenough in time that the presence of one alters the biological effects ofthe other. The two compounds may be administered simultaneously (i.e.,concurrently) or sequentially. Simultaneous administration may becarried out by mixing the compounds prior to administration, or byadministering the compounds at the same point in time but at differentanatomic sites or using different routes of administration.

The term “pharmaceutically acceptable prodrugs” as used herein refers tothose prodrugs of the compounds of the present invention which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of humans and lower animals without undue toxicity,irritation, allergic response and the like, commensurate with areasonable risk/benefit ratio, and effective for their intended use, aswell as the zwitterionic forms, where possible, of the compounds of theinvention. The term “prodrug” refers to compounds that are rapidlytransformed in vivo to yield the parent compound of the above formulae,for example, by hydrolysis in blood. A thorough discussion is providedin T. Higuchi and V. Stella, Prodrugs as Novel delivery Systems, Vol. 14of the A.C.S. Symposium Series and in Edward B. Roche, ed.,Bioreversible Carriers in Drug Design, American PharmaceuticalAssociation and Pergamon Press, 1987, both of which are incorporated byreference herein. See also U.S. Pat. No. 6,680,299 Examples include aprodrug that is metabolized in vivo by a subject to an active drughaving an activity of active compounds as described herein, wherein theprodrug is an ester of an alcohol or carboxylic acid group, if such agroup is present in the compound; an acetal or ketal of an alcoholgroup, if such a group is present in the compound; an N-Mannich base oran imine of an amine group, if such a group is present in the compound;or a Schiff base, oxime, acetal, enol ester, oxazolidine, orthiazolidine of a carbonyl group, if such a group is present in thecompound, such as described in U.S. Pat. No. 6,680,324 and U.S. Pat. No.6,680,322.

“Non-steroidal Antiinflammatory Drugs” (NSAID) are known in bothconjugated and unconjugated form. See, e.g., U.S. Pat. Nos. 6,355,666and 6,306,842. Suitable examples include, but are not limited to,aspirin, indomethacin, ibuprofen, fenoprofen, sulindac, naproxen,tolmetin, mefanamic acid, mefclofenamic acid, etc.

“Beta blockers” as used herein are known. See, e.g., U.S. Pat. Nos.7,005,425 and 6,756,408. Examples include, but are not limited toatenolol, pindolol, esmolol, propranolol, metoprolol, etc.

“Cardiovascular disease” as used herein includes, but is not limited to,thrombosis, congestive heart failure, vasoconstriction, cardiachypertrophy, arrhythmia, heart attack, hypertension, etc.

“Congestive heart failure” as described herein may be due to any cause,including but not limited to coronary artery disease, myocardialinfarction, high blood pressure, heart valve disease, congenital heartdefects, endocarditis, myocarditis, or any combination thereof.

The disclosures of all United States patent references cited herein areincorporated herein by reference in their entirety.

1. Active Compounds.

Active compounds of the present invention are, in general, compounds ofFormula I:

wherein:

R₁ and R₂ are each independently C1-C4 alkyl;

or R₁ and R₂ together form a C2-C7 alkylene chain; and

Z is a non-steroidal anti-inflammatory drug;

and pharmaceutically acceptable salts and prodrugs thereof.

In other embodiments, active compounds of the present invention arecompounds of Formula (III):

wherein:

R₁ and R₂ are each independently C1-C4 alkyl;

or R₁ and R₂ together form a C2-C7 alkylene chain; and

R₃ is C1-C5 alkyl, haloalkyl or aryl,

or a pharmaceutically acceptable salt or prodrug thereof.

Compounds of Formula I or III may be made in accordance with thetechniques described herein, or variations thereof that will be apparentto those skilled in the art based upon the instant disclosure. Ingeneral, compounds of Formula I of the invention may be produced byreacting a compound of Formula II:

wherein R₁ and R₂ are as given in connection with formula I above, witha NSAID (preferably a NSAID containing a carboxylic acid group) in thepresence of an oxidant and an acid to produce the compound of Formula I.Alternatively, the acid can be substituted by using excess of NSAID.Reaction conditions are not critical. The reaction may be carried out inany suitable organic solvent such as methylene chloride, chloroform,acetic acid, ethyl acetate, diethyl ether, tetrahydrofuran, benzene, ortoluene. Reaction temperature can vary from 0° C. to 30° C. Commonoxidants of oximes may be used to carry out this reaction such as leadtetraacetate (LTA), (diacyloxyiodo) benzenes, periodates, Dess-Martineperodinane or Swern conditions in the presence of carboxylic acid.Particularly, the method of using (diacyloxyiodo) benzenes to produceacyloxy nitroso compounds has been reported in Zhutov, et. al. RussianJournal of Organic Chem. 2003, 39, 1672-1673 and Calvet, et. al.,Organic Letters, 2004, 6, 2449. Additionally, other (diacyloxyiodo)benzenes may be also be used in the reaction. When periodates,especially sodium periodate, is used in the reaction, water or alcoholmay be used as a reaction solvent.

An alternative method to prepare the acyloxy nitroso compounds isacylation of the anion of a nitro compound followed by a [3,2]sigmatropic rearrangement, which is described in Danieko, V. I., Russ.J. Org. Chem. 2002, 38, 1431-1433.

Examples of compounds of the present invention include, but are notlimited to, those conjugates shown adjacent the corresponding NSAID asset forth below:

NSAID Corresponding Conjugate

wherein R₁ and R₂ are as given above.

Examples of compounds of Formula III include, but are not limited to:

The active compounds disclosed herein can, as noted above, be preparedin the form of their pharmaceutically acceptable salts or prodrugs.Pharmaceutically acceptable salts are salts that retain the desiredbiological activity of the parent compound and do not impart undesiredtoxicological effects. Examples of such salts are (a) acid additionsalts formed with inorganic acids, for example hydrochloric acid,hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid and thelike; and salts formed with organic acids such as, for example, aceticacid, oxalic acid, tartaric acid, succinic acid, maleic acid, fumaricacid, gluconic acid, citric acid, malic acid, ascorbic acid, benzoicacid, tannic acid, palmitic acid, alginic acid, polyglutamic acid,naphthalenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid,naphthalenedisulfonic acid, polygalacturonic acid, and the like; (b)salts formed from elemental anions such as chlorine, bromine, andiodine, and (c) salts derived from bases, such as ammonium salts, alkalimetal salts such as those of sodium and potassium, alkaline earth metalsalts such as those of calcium and magnesium, and salts with organicbases such as dicyclohexylamine and N-methyl-D-glucamine.

2. Pharmaceutical Formulations.

The active compounds described above may be formulated foradministration in a pharmaceutical carrier in accordance with knowntechniques. See, e.g., Remington, The Science And Practice of Pharmacy(9^(th) Ed. 1995). In the manufacture of a pharmaceutical formulationaccording to the invention, the active compound (including thephysiologically acceptable salts thereof) is typically admixed with,inter alia, an acceptable carrier. The carrier must, of course, beacceptable in the sense of being compatible with any other ingredientsin the formulation and must not be deleterious to the patient. Thecarrier may be a solid or a liquid, or both, and is preferablyformulated with the compound as a unit-dose formulation, for example, atablet, which may contain from 0.01 or 0.5% to 95% or 99% by weight ofthe active compound. One or more active compounds may be incorporated inthe formulations of the invention, which may be prepared by any of thewell known techniques of pharmacy comprising admixing the components,optionally including one or more accessory ingredients.

The formulations of the invention include those suitable for oral,rectal, topical, buccal (e.g., sub-lingual), vaginal, parenteral (e.g.,subcutaneous, intramuscular, intradermal, or intravenous), topical(i.e., both skin and mucosal surfaces, including airway surfaces) andtransdermal administration, although the most suitable route in anygiven case will depend on the nature and severity of the condition beingtreated and on the nature of the particular active compound which isbeing used.

Formulations suitable for oral administration may be presented indiscrete units, such as capsules, cachets, lozenges, or tablets, eachcontaining a predetermined amount of the active compound; as a powder orgranules; as a solution or a suspension in an aqueous or non-aqueousliquid; or as an oil-in-water or water-in-oil emulsion. Suchformulations may be prepared by any suitable method of pharmacy whichincludes the step of bringing into association the active compound and asuitable carrier (which may contain one or more accessory ingredients asnoted above). In general, the formulations of the invention are preparedby uniformly and intimately admixing the active compound with a liquidor finely divided solid carrier, or both, and then, if necessary,shaping the resulting mixture. For example, a tablet may be prepared bycompressing or molding a powder or granules containing the activecompound, optionally with one or more accessory ingredients. Compressedtablets may be prepared by compressing, in a suitable machine, thecompound in a free-flowing form, such as a powder or granules optionallymixed with a binder, lubricant, inert diluent, and/or surfaceactive/dispersing agent(s). Molded tablets may be made by molding, in asuitable machine, the powdered compound moistened with an inert liquidbinder.

Formulations suitable for buccal (sub-lingual) administration includelozenges comprising the active compound in a flavoured base, usuallysucrose and acacia or tragacanth; and pastilles comprising the compoundin an inert base such as gelatin and glycerin or sucrose and acacia.

Formulations of the present invention suitable for parenteraladministration comprise sterile aqueous and non-aqueous injectionsolutions of the active compound, which preparations are preferablyisotonic with the blood of the intended recipient. These preparationsmay contain anti-oxidants, buffers, bacteriostats and solutes whichrender the formulation isotonic with the blood of the intendedrecipient. Aqueous and non-aqueous sterile suspensions may includesuspending agents and thickening agents. The formulations may bepresented in unit\dose or multi-dose containers, for example sealedampoules and vials, and may be stored in a freeze-dried (lyophilized)condition requiring only the addition of the sterile liquid carrier, forexample, saline or water-for-injection immediately prior to use.Extemporaneous injection solutions and suspensions may be prepared fromsterile powders, granules and tablets of the kind previously described.For example, in one aspect of the present invention, there is providedan injectable, stable, sterile composition comprising a compound ofFormula (I), or a salt thereof, in a unit dosage form in a sealedcontainer. The compound or salt is provided in the form of alyophilizate which is capable of being reconstituted with a suitablepharmaceutically acceptable carrier to form a liquid compositionsuitable for injection thereof into a subject. The unit dosage formtypically comprises from about 10 mg to about 10 grams of the compoundor salt. When the compound or salt is substantially water-insoluble, asufficient amount of emulsifying agent which is physiologicallyacceptable may be employed in sufficient quantity to emulsify thecompound or salt in an aqueous carrier. One such useful emulsifyingagent is phosphatidyl choline.

Formulations suitable for rectal administration are preferably presentedas unit dose suppositories. These may be prepared by admixing the activecompound with one or more conventional solid carriers, for example,cocoa butter, and then shaping the resulting mixture.

Formulations suitable for topical application to the skin preferablytake the form of an ointment, cream, lotion, paste, gel, spray, aerosol,or oil. Carriers which may be used include petroleum jelly, lanoline,polyethylene glycols, alcohols, transdermal enhancers, and combinationsof two or more thereof.

Formulations suitable for transdermal administration may be presented asdiscrete patches adapted to remain in intimate contact with theepidermis of the recipient for a prolonged period of time. Formulationssuitable for transdermal administration may also be delivered byiontophoresis (see, for example, Pharmaceutical Research 3 (6):318(1986)) and typically take the form of an optionally buffered aqueoussolution of the active compound. Suitable formulations comprise citrateor bis\tris buffer (pH 6) or ethanol/water and contain from 0.1 to 0.2Mactive ingredient.

Further, the present invention provides liposomal formulations of thecompounds disclosed herein and salts thereof. The technology for formingliposomal suspensions is well known in the art. When the compound orsalt thereof is an aqueous-soluble salt, using conventional liposometechnology, the same may be incorporated into lipid vesicles. In such aninstance, due to the water solubility of the compound or salt, thecompound or salt will be substantially entrained within the hydrophiliccenter or core of the liposomes. The lipid layer employed may be of anyconventional composition and may either contain cholesterol or may becholesterol-free. When the compound or salt of interest iswater-insoluble, again employing conventional liposome formationtechnology, the salt may be substantially entrained within thehydrophobic lipid bilayer which forms the structure of the liposome. Ineither instance, the liposomes which are produced may be reduced insize, as through the use of standard sonication and homogenizationtechniques.

Of course, the liposomal formulations containing the compounds disclosedherein or salts thereof, may be lyophilized to produce a lyophilizatewhich may be reconstituted with a pharmaceutically acceptable carrier,such as water, to regenerate a liposomal suspension.

Other pharmaceutical compositions may be prepared from thewater-insoluble compounds disclosed herein, or salts thereof, such asaqueous base emulsions. In such an instance, the composition willcontain a sufficient amount of pharmaceutically acceptable emulsifyingagent to emulsify the desired amount of the compound or salt thereof.Particularly useful emulsifying agents include phosphatidyl cholines,and lecithin.

In addition to compounds of formula (I) or their salts, thepharmaceutical compositions may contain other additives, such aspH-adjusting additives. In particular, useful pH-adjusting agentsinclude acids, such as hydrochloric acid, bases or buffers, such assodium lactate, sodium acetate, sodium phosphate, sodium citrate, sodiumborate, or sodium gluconate. Further, the compositions may containmicrobial preservatives. Useful microbial preservatives includemethylparaben, propylparaben, and benzyl alcohol. The microbialpreservative is typically employed when the formulation is placed in avial designed for multidose use. Of course, as indicated, thepharmaceutical compositions of the present invention may be lyophilizedusing techniques well known in the art.

3. Dosage and Routes of Administration.

As noted above, the present invention provides pharmaceuticalformulations comprising the active compounds (including thepharmaceutically acceptable salts thereof), in pharmaceuticallyacceptable carriers for oral, rectal, topical, buccal, parenteral,intramuscular, intradermal, or intravenous, and transdermaladministration.

Preferred routes of parenteral administration include oral, transdermal,and parenteral, injection.

The therapeutically effective dosage of any specific compound, the useof which is in the scope of present invention, will vary somewhat fromcompound to compound, and patient to patient, and will depend upon thecondition of the patient and the route of delivery. As a generalproposition, a dosage from about 0.1 to about 50 mg/kg will havetherapeutic efficacy, with all weights being calculated based upon theweight of the active compound, including the cases where a salt isemployed. Toxicity concerns at the higher level may restrict intravenousdosages to a lower level such as up to about 10 mg/kg, with all weightsbeing calculated based upon the weight of the active base, including thecases where a salt is employed. A dosage from about 10 mg/kg to about 50mg/kg may be employed for oral administration. Typically, a dosage fromabout 0.5 mg/kg to 5 mg/kg may be employed for intramuscular injection.Preferred dosages are 1 μmol/kg to 50 μmol/kg, and more preferably 22μmol/kg and 33 μmol/kg of the compound for intravenous or oraladministration. The duration of the treatment is usually once per dayfor a period of two to three weeks or until the condition is essentiallycontrolled. Lower doses given less frequently can be usedprophylactically to prevent or reduce the incidence of recurrence of theinfection.

4. Combination Treatments.

In another embodiment, it is envisioned to use an active compound of theinvention in combination with other therapeutic modalities, in likemanner as described in U.S. Pat. No. 6,946,441 to Long et al. Thus, inaddition to the therapies described above, one may also provide to thepatient more “standard” pharmaceutical cardiac therapies. Examples ofstandard therapies include, without limitation, so-called “betablockers,” anti-hypertensives, cardiotonics, anti-thrombotics,vasodilators, hormone antagonists, iontropes, diuretics, endothelinantagonists, calcium channel blockers, phosphodiesterase inhibitors, ACEinhibitors, angiotensin type 2 antagonists and cytokineblockers/inhibitors.

Combinations may be achieved by contacting cardiac cells with a singlecomposition or pharmacological formulation that includes both agents, orby contacting the cell with two distinct compositions or formulations,at the same time, wherein one composition includes the expressionconstruct and the other includes the agent. Alternatively, the activecompound of the invention may precede or follow administration of theother agent by intervals ranging from minutes to weeks. In embodimentswhere the other agent and expression construct are applied separately tothe cell, one would generally ensure that a significant period of timedid not expire between the time of each delivery, such that the agentand expression construct would still be able to exert an advantageouslycombined effect on the cell. In such instances, it is contemplated thatone would typically contact the cell with both modalities within about12-24 hours of each other and, more preferably, within about 6-12 hoursof each other, with a delay time of only about 12 hours being mostpreferred. In some situations, it may be desirable to extend the timeperiod for treatment significantly, however, where several days (2, 3,4, 5, 6 or 7) to several weeks (1, 2, 3, 4, 5, 6, 7 or 8) lapse betweenthe respective administrations.

It also is conceivable that more than one administration of either anactive compound of the invention, or the other agent will be desired. Inthis regard, various combinations may be employed. By way ofillustration, where the active compound is “A” and the other agent is“B”, the following permutations based on 3 and 4 total administrationsare exemplary:

-   -   A/B/A B/A/B B/B/A A/A/B B/A/A A/B/B B/B/B/A B/B/A/B A/A/B/B        A/B/A/B A/B/B/A B/B/A/A B/A/B/A B/A/A/B B/B/B/A A/A/A/B B/A/A/A        A/B/A/A A/A/B/A A/B/B/B B/A/B/B B/B/A/B        Other combinations are likewise contemplated.

The present invention is explained in great detail in the followingnon-limiting Examples.

Example 1 1-Acetoxy-1-nitrosocyclohexane

A solution of cyclohexanone oxime (5.46 g, 48.25 mmol) in methylenechloride (50 mL) was added dropwise with stirring to a solution of LTA(21.39 g, 48.25 mmol) in methylene chloride (100 mL) at 0° C. A bluecolor gradually appeared with the addition of the oxime. After 1 h at 0°C., the reaction mixture was warmed to room temperature. After 2 h atroom temperature, water (30 mL) was added and the organic layer wasextracted with water (2×30 mL) and saturated sodium bicarbonate solution(2×30 mL). The organic layer was dried over Na₂SO₄, the solventevaporated and the residue purified by column chromatography to give1-Acetoxy-1-nitrosocyclohexane as a bright blue liquid (52% yield):R_(f) 0.68 (pentane/ethyl acetate=20:1); ¹H NMR (300 MHz, Benzene-d₆) δ1.1-1.9 (m, 13H); ¹³C NMR (300 MHz, Benzene-d₆) δ 21.0 (CH₂), 22.0(2CH₂), 25.1 (2CH₂), 29.7 (CH₃), 123.8 (O—C—N), 168.5 (C═O). UV/vis(MeOH): λ_(max)=667 nm. IR (KBr): v=1750 cm⁻¹ (C═O), 1561 cm⁻¹ (N═O).

Example 2 1-Nitroso-1-para-nitrobenzoxycyclohexane

A solution of cyclohexanone oxime (2.66 g, 23.51 mmol) in methylenechloride (50 mL) was added dropwise with stirring to a solution of LTA(10.42 g, 23.51 mmol) and 4-nitrobenzoic acid (39.29 g, 235.1 mmol) inmethylene chloride (300 mL) at 0° C. A blue color gradually appearedwith the addition of the oxime. After 1 h at 0° C., the reaction mixturewas warmed to room temperature. After 3 h at room temperature, water (50mL) was added and the organic layer was extracted with water (2×50 mL)and 3% sodium bicarbonate solution (2×50 mL). The organic layer wasdried over Na₂SO₄, the solvent evaporated and the residue wasrecrystallized in diethyl ether/petroleum ether (1:1) in a −5° C.freezer to give 1-Nitroso-1-para-nitrobenzoxycyclohexane as bright bluecrystals (20-25% yield): R_(f) 0.55 (pentane/ethyl acetate=20:1); ¹H NMR(300 MHz, Benzene-d₆) δ 1.17-2.04 (m, 10H), 7.38-7.98 (d, 4H); ¹³C NMR(300 MHz, Benzene-d₆) δ 22.1 (2CH₂), 25.0 (CH₂), 29.7 (2CH₂), 123.8(2Ph-CH), 125.3 (O—C—N), 131.1 (2Ph-CH), 135.3 (Ph-C), 151.1 (Ph-C),162.6 (C═O).

Example 3 1-Nitroso-1-para-nitrobenzoxypropane

A solution of cyclohexanone oxime (3.11 g, 42.58 mmol) in methylenechloride (50 mL) was added dropwise with stirring to a solution of LTA(18.88 g, 42.58 mmol) and 4-nitrobenzoic acid (71.16 g, 425.8 mmol) inmethylene chloride (300 mL) at 0° C. A blue color gradually appearedwith the addition of the oxime. After 1 h at 0° C., the reaction mixturewas warmed to room temperature. After 3 h at room temperature, water (50mL) was added and the organic layer was extracted with water (2×50 mL)and 3% sodium bicarbonate solution (2×50 mL). The organic layer wasdried over Na₂SO₄, the solvent evaporated and the residue wasrecrystallized in diethyl ether/petroleum ether (1:1) in a −5° C.freezer to give 1-Nitroso-1-para-nitrobenzoxypropane as bright bluecrystals (25-30% yield): R_(f) 0.5 (pentane/ethyl acetate=20:1); ¹H NMR(300 MHz, CDCl₃) δ 1.69 (s, 6H), 8.31-8.48 (d, 4H); ¹³C NMR (300 MHz,CDCl₃) δ 21.1 (2CH₃), 122.6 (O—C—N), 124.0 (2Ph-CH), 131.4 (2Ph-CH),135.6 (Ph-C), 151.2 (Ph-C), 162.9 (C═O).

Example 4 1-Nitroso-1-trifluoroacetoxycyclohexane

A solution of cyclohexanone oxime (4.88 g, 43.16 mmol) in methylenechloride (50 mL) was added dropwise with stirring to a solution of LTA(19.14 g, 43.16 mmol) and trifluoroacetic acid (49.22 g, 431.6 mmol) inmethylene chloride (200 mL) at 0° C. A blue color gradually appearedwith the addition of the oxime. After 1 h at 0° C., the reaction mixturewas warmed to room temperature. After 3 h at room temperature, water (50mL) was added and the organic layer was extracted with water (2×50 mL).The organic layer was dried over Na₂SO₄, the solvent evaporated and theresidue was purified by column chromatography to give1-Nitroso-1-trifluoroacetoxycyclohexane as a bright blue liquid (30%yield): R_(f) 0.57 (pentane); ¹H NMR (300 MHz, Benzene-d₆) δ 1.1-1.9 (m,10H); ¹³C NMR (300 MHz, Benzene-d₆) δ 19.9 (2CH₂), 22.9 (CH₂), 27.4(2CH₂), 113.8 (q, J=286.2 Hz), 127.2 (O—C—N), 153.7 (q, J=42.5 Hz); ¹⁹FNMR (300 MHz, Benzene-d₆) δ −75.7 (CF₃).

Example 5 1-Nitroso-1-ortho-Acylbenzoxypropane

A solution of acetone oxime (4.03 g, 55.12 mmol) in methylene chloride(50 mL) was added dropwise with stirring to a solution of LTA (24.44 g,55.12 mmol) and aspirin (99.0 g, 551.2 mmol) in methylene chloride (500mL) at 0° C. A blue color gradually appeared with the addition of theoxime. After 1 h at 0° C., the reaction mixture was warmed to roomtemperature. After 3 h, the reaction mixture was filtered and thefiltrate was extracted with water (3×100 mL). The organic layer wasdried over Na₂SO₄, the solvent evaporated and the residue was purifiedby column chromatography to give the1-Nitroso-1-ortho-Acylbenzoxypropane as a blue solid. (10% yield): R_(f)0.45 (pentane/ethyl acetate=10:1); UV/vis (MeOH): λ_(max)=659 nm; IR(KBr): ν_(C═O)=1768 cm⁻¹, ν_(C═O)=1731 cm⁻¹, ν_(N═O)=1572 cm⁻¹; 1H NMR(300 MHz, Benzene-d₆): δ 1.2 (s, 6H), 2.0 (s, 3H), 6.91-6.99 (m, 2H),7.11-7.17 (dd, 1H, J1=7.7 Hz, J2=1.7 Hz), 8.13-8.16 (m, 1H); ¹³C NMR(300 MHz, Benzene-d₆): δ 20.6 (2CH₃), 25.4 (CH₃), 121.8 (O—C—N), 124.0(Ph-C), 124.5 (Ph-CH), 126.3 (Ph-CH), 132.1 (Ph-CH), 134.6 (Ph-CH),151.9 (Ph-C), 163.0 (C═O), 169.2 (C═O).

Example 6

General Example of Using (Diacetoxyiodo) Benzene as Oxidants

(Diacetoxyiodo) benzene (1.2 mol equivalents) was added to a solution ofoxime (1 mol equivalent) in methylene chloride at 0° C. under argon withstirring. After 2 hour, the reaction mixture was poured into a saturatedaqueous solution of sodium bicarbonate. The layers were separated andthe aqueous layer was re-extracted with methylene chloride. The organiclayers were combined, dried over magnesium sulfate, filtered andconcentrated to give a blue acyloxy nitroso compound that can bepurified by flash chromatography or in some cases distillation orrecrystallization. Individual reactions might require variations, whichare apparent to those skilled in the art based upon the general example.

Example 7 General Example of Preparing Acyloxy Nitroso Compounds byAcylation of the Anion of a Nitro Compound Followed by a [3,2]Sigmatropic Rearrangement

A nitro compound (1 mol equivalent) would be added slowly to asuspension of potassium t-butoxide (1 mol equivalent) in dry diethylether under argon at 0° C. with stirring. After 30 min, acetic anhydride(1 mol equivalent) was added slowly over 25 minutes and the mixture wasstirred. After 2 h, the mixture was filtered and the precipitate waswashed with diethyl ether until the diethyl ether was colorless. Theblue filtrate was concentrated to give a blue oil that was purified byeither flash chromatography, distillation or recrystallization.Individual reactions might require variations, which are apparent tothose skilled in the art based upon the general example.

The foregoing is illustrative of the present invention, and is not to beconstrued as limiting thereof. The invention is defined by the followingclaims, with equivalents of the claims to be included therein.

1. A compound of Formula I:

wherein: R₁ and R₂ are each independently C1-C4 alkyl; or R₁ and R₂together form a C2-C7 alkylene chain; and Z is a non-steroidalanti-inflammatory drug (NSAID); or a pharmaceutically acceptable salt orprodrug thereof.
 2. A compound of claim 1 having the structure:

or a pharmaceutically acceptable salt or prodrug thereof.
 3. Acomposition comprising a compound of claim 1 in a pharmaceuticallyacceptable carrier.
 4. A method of treating a cardiovascular disorder ina subject in need thereof, comprising administering said subject atreatment-effective amount of a compound of claim
 1. 5. The method ofclaim 4, wherein said cardiovascular disorder is congestive heartfailure.
 6. The method of claim 4, further comprising concurrentlyadministering a beta blocker to said subject in a treatment-effectiveamount.
 7. A method of treating gastrointestinal side effects associatedwith NSAID treatment in a subject in need thereof, comprisingadministering said subject a treatment-effective amount of a compound ofclaim
 1. 8. A pharmaceutical composition for treating congestive heartfailure, comprising, in combination, a pharmaceutically acceptablecarrier and a treatment effective amount of a compound of Formula (III):

wherein: R₁ and R₂ are each independently C1-C4 alkyl; or R₁ and R₂together form a C2-C7 alkylene chain; and R₃ is C1-C5 alkyl, haloalkylor aryl, or a pharmaceutically acceptable salt or prodrug thereof. 9.The composition of claim 8, wherein said cardiovascular disorder iscongestive heart failure.
 10. The composition of claim 8 wherein saidcomposition is an injectable composition.
 11. The composition of claim 8wherein said composition is tablet or capsule.
 12. The composition ofclaim 8, wherein said compound is selected from the group consisting of

or a pharmaceutically acceptable salt or prodrug thereof.
 13. A methodof treating or congestive heart failure in a subject in need thereof,comprising administering said subject a treatment effective amount of acompound of Formula (III):

wherein: R₁ and R₂ are each independently C1-C4 alkyl; or R₁ and R₂together form a C2-C7 alkylene chain; and R₃ is C1-C5 alkyl, haloalkylor aryl, or a pharmaceutically acceptable salt or prodrug thereof. 14.The method of claim 13, further comprising concurrently administering abeta blocker to said subject in a treatment effective amount.
 15. Themethod of claim 13, wherein said compound is selected from the groupconsisting of:

or a pharmaceutically acceptable salt or prodrug thereof.
 16. The methodof claim 13 wherein said congestive heart failure is caused by coronaryartery disease, myocardial infarction, high blood pressure, heart valvedisease, congenital heart defects, endocarditis, myocarditis, or anycombination thereof.
 17. The method of claim 13, wherein saidadministering step is carried out by parenteral injection or oraladministration.